Complications of cardiovascular disease, such as myocardial infarction, stroke, and peripheral vascular disease account for half of all deaths in the United States. A high level of low density lipoprotein (LDL) in the bloodstream has been linked to the formation of coronary lesions which obstruct the flow of blood and promote thrombosis. (See Goodman and Gilman, The Pharmacological Basis of Therapeutics, 9th ed., p. 879 (1996)). Reducing plasma LDL levels has been shown to reduce the risk of clinical events in patients with cardiovascular disease and in patients who are free of cardiovascular disease but who have hypercholesterolemia. (Scandinavian Simvastatin Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b.)
Statin drugs are currently the most therapeutically effective drugs available for reducing the level of LDL in the blood stream of a patient at risk for cardiovascular disease. This class of drugs includes, inter alia, compactin, lovastatin, simvastatin, pravastatin and fluvastatin.
The mechanism of action of statin drugs has been elucidated in some detail. The statin drugs disrupt the synthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme (“HMG-CoA reductase”). HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is the rate determining step in the biosynthesis of cholesterol. Consequently, HMG-CoA reductase inhibition leads to a reduction in the rate of formation of cholesterol in the liver. Decreased production of cholesterol causes an increase in the number of LDL receptors and corresponding reduction in the concentration of LDL particles in the bloodstream. Reduction in the LDL level in the bloodstream reduces the risk of coronary artery disease. (J.A.M.A. 1984; 251: 351-74).
Currently available statins include: lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin and atorvastatin, which are administered in their lactone form, as sodium salts, or as calcium salts.
Rosuvastatin (7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid) calcium, an HMG-CoA reductase inhibitor, can lower LDL-cholesterol and triglycerides levels more effectively than first generation statin drugs. Rosuvastatin calcium has the following chemical formula:

A number of processes for the preparation of rosuvastatin and salts thereof are disclosed. Rosuvastatin calcium, intermediates of rosuvastatin, and their preparation are disclosed in U.S. Pat. No. 5,260,440, herein the '440 patent. WO 03/097614 discloses the synthesis of rosuvastatin from the late intermediate methyl (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenyl-phosphoranylidene hexanate, an intermediate disclosed in the '440 patent. WO 03/087112 discloses the synthesis of rosuvastatin from a different intermediate, t-butyl (3R)-3-(t-butyldimethylsilyloxy)-6-dimethoxyphosphinyl-5-oxohexanate. WO/0049014 discloses the synthesis of rosuvastatin using intermediates with other side chains via a Wittig reaction. EP 850,902 discloses the removal of triphenylphosphine derivatives in mixtures.
Other intermediates and their preparation are also described in, e.g. U.S. Pat. No. 5,354,879, which discloses the purification by column chromatography of the intermediate methyl-(3R)-3-(tert-butyldimethylsilyloxy)-6-dimethoxyphosphinyl-5-oxohexanoate, which is obtained as an oily residue. This intermediate and its preparation are also mentioned in U.S. Pat. No. 5,717,124.
WO 03/087112 discloses a process for the preparation of t-butyl (3R)-3-(t-butyldimethylsilyloxy)-6-dimethoxyphosphinyl-5-oxohexanoate, which yields a product having a purity of 99.5%, obtained by silica gel column chromatography.
Like any synthetic compound, rosuvastatin calcium can contain extraneous compounds or impurities that can come from many sources. These can include unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in rosuvastatin or any active pharmaceutical ingredient (API) are undesirable, and, in extreme cases, might even be harmful to a patient being treated with a dosage form of the API in which a sufficient amount of impurities is present.
There remains a need in the art for cost effective and industrial scale preparation processes of preparing rosuvastatin intermediates.